The gp120 and gp41 envelope glycoproteins of human immunodeficiency virus (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), plays important roles in virus entry into target cells and viral cytopathic effects. Since the HIV-1 envelope glycoproteins are exposed on the virion, they represent critical targets for therapeutic intervention and vaccine development. Antibodies that neutralize virus infectivity in vitro and that, in some cases, have been shown to be protective in vivo are directed against both variable and conserved regions of the HIV-1 envelope glycoproteins. The relatively well- conserved discontinuous epitopes on the HIV-1 gp120 glycoprotein constitute attractive targets for immunological intervention, but have been proven difficult to elicit antibodies against. The goal of this proposal is to capitalize on new information about the improved immunogenicity. The specific aims of this proposal are: 1) To define precisely, by a combination of mutagenic and structural analyses, the conserved HIV-1 neutralization epitopes; 2) To examine the effect of removal of V1 and V2 variable loops on the immunogenicity of the HIV-1 envelope glycoproteins; and 3)To determine whether stabilization of particular native HIV-1 envelope glycoprotein structures improves immunogenicity.